This project aims to develop an understanding of the mechanisms by which retinoids suppress the development of cancer in the mammalian cutaneous epidermis. The objective is to assess the role, if any, of metaplastic differentiation in the retinoid-mediated neutralization of tumor promotion by phorbol esters. The biological vehicle for the study will be a primary (or early passage) culture of fetal murine epidermal keratinocytes which can differentiate toward keratinization as occurs in situ or, in the presence of a minimal concentration of retinoid, can exhibit metaplastic differentiation (i.e. absence of tonofilaments and desmosomes, loss of cell to cell contact, and appearance of microvilli and "periderm-like" granules). Molecular "markers" (i.e. proteins) for each pathway will be developed and monitored to quantify the differentiative state of the tissue under the various experimental conditions to be employed. The specific aims of the project are to obtain answers to the following questions: Do retinoids exert their influence toward metaplastic development only on cells of the germinative population or also on cells already keratinizing? Is the participation of retinoids in glycosyl transfer reactions involved in the regulation of differentiative direction? What is the molecular mechanism by which this regulation occurs? Does retinoid-mediated metaplastic development neutralize tumor promotion because the metaplastic pathway does not require action by carcinogenically-initiated genes on the "keratinization" pathway?